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Endometrial Cancer Prevention (PDQ®)

Description of Evidence

Background

Incidence and mortality

Endometrial cancer is the most common invasive gynecologic cancer in U.S. women, with an estimated 54,870 new cases expected to occur in 2015.[1] This disease primarily affects postmenopausal women at an average age of 60 years at diagnosis.[2] In the United States, it is estimated that approximately 10,170 women will die of endometrial cancer in 2015. From 2007 to 2011, incidence rates of endometrial cancer increased by 2.4% per year. During that same time, death rates from endometrial cancer increased by 1.9% per year.[1]

In the mid-1970s, the diagnosis of approximately 15,000 cases of postmenopausal endometrial cancers in excess of those expected on the basis of the underlying secular trend, has been related to the use of postmenopausal estrogen therapy.[3] Additional risk factors may be related to estrogenic effects, including obesity, polycystic ovarian syndrome, tamoxifen use, and reproductive factors such as nulliparity, early menarche, and late menopause.

Women with hereditary nonpolyposis colorectal cancer (HNPCC) syndrome have a markedly increased risk of endometrial cancer compared with women in the general population. Among women who are HNPCC mutation carriers, the estimated cumulative incidence of endometrial cancer ranges from 20% to 60%.[4,5]

Factors that have been associated with a decreased incidence of endometrial cancer include parity, lactation, use of combined oral contraceptives, a diet low in fat and high in plant foods, and physical activity.

Interventions Associated With Decreased Risk

Oral contraceptives

Use of combination oral contraceptives (COC) for at least 1 year reduces endometrial cancer risk by approximately 40%, as demonstrated by case-control studies and prospective cohort studies.[8-10] This decrease in risk persists for at least 15 years after discontinuation of COCs. A meta-analysis of ten case-control studies and one prospective study found an association between risk reduction and duration of use. Overall, 4 years of COC use was associated with a risk reduction of approximately 56%; 8 years, 67%; and 12 years, 72%. The single-prospective study did not show a duration response, but the risk was reduced by 80% after 9 years of follow-up.[11]

A Swedish population-based case-control study confirms these findings. Women who used any type of oral contraceptive had a 30% risk reduction (odds ratio [OR], 0.7; 95% CI, 0.5–0.9) and women who used progestin-only pills had a 60% risk reduction (OR, 0.4; 95% CI, 0.2–1.4). Women who used COCs for at least 3 years had a 50% risk reduction (OR, 0.5; 95% CI, 0.3–0.7) and those who used COCs for at least 10 years had an 80% risk reduction (OR, 0.2; 95% CI, 0.1–0.4). Overall, risk decreased by 10% per year of COC use and was observed for atypical hyperplasias as well as all grades of invasive tumors.[12]

Physical activity

Several cohort [13,14] and case-control [15-23] studies of physical activity and endometrial cancer reveal a weak to moderate inverse relationship, despite varying methods of assessing physical activity levels. For postmenopausal women enrolled in The Netherlands Cohort Study on Diet and Cancer, a 46% reduction (RR, 0.54; 95% CI, 0.34–0.85; P = .002) in risk of endometrial cancer was reported in those women who were physically active 90 minutes or more per day compared with less than 30 minutes each day.[24] One case-control study of 822 endometrial cancer cases and 1,111 population controls showed that regular exercise was associated with a 38% decrease in risk (OR, 0.62; 95% CI, 0.51–0.76) without a trend for increasing duration or intensity of physical activity.[25] The Breast Cancer Detection Project Follow-up Study, using a prospective cohort, did not confirm an association between recent physical activity levels and risk.[26] It is unknown whether physical activity reduces endometrial cancer risk by reducing obesity, by reducing serum estrone levels, or by another mechanism.[27]

Factors Associated With Decreased Risk

Increasing parity and lactation

Decreased risk of endometrial cancer is associated with parity and lactation, perhaps by inhibiting ovulation. A case-control study conducted in Mexico City, among low-risk women, indicates a 58% to 72% reduction in risk of endometrial cancer associated with increasing duration of lactation. A significant trend was seen for duration of lactation and for the number of children breastfed.[28] A population-based case-control study, comparing Wisconsin women who breastfed for at least 2 weeks versus those who did not, was negative (OR, 0.90; 95% CI, 0.72–1.13). Increasing duration of lactation was not associated with a decrease in disease risk, but breastfeeding within the past three decades was associated with reduced risk (OR, 0.58; 95% CI, 0.36–0.96), as was the first breastfeeding after age 30 years (95% CI, 0.28–0.90).[29] The European Prospective Investigation into Cancer and Nutrition observed a decreased risk associated with parity compared with nulliparous women (hazard ratio, 0.65; 95% CI, 0.54–0.77) with a trend of decreasing risk with increasing number of full-term pregnancies (P < .0001). While breastfeeding for more than 18 months was associated with a decreased risk, the association attenuated and was no longer statistically significant after adjusting for the numbers of full-term pregnancies.[30]

Factors Associated With Increased Risk

Endogenous estrogen

Reproductive factors resulting in increased duration of exposure to endogenous estrogen, such as early menarche, nulliparity, and late menopause, are associated with an increased risk of endometrial cancer. Other factors associated with increased risk, such as obesity and polycystic ovary syndrome, may also be related to increased estrogen exposure.

The first prospective investigation of endogenous estrogens and the risk of endometrial cancer was a case-control study nested within the New York University Women’s Health Study.[31] Results suggest an increased risk of endometrial cancer associated with postmenopausal levels of endogenous hormones including estradiol, percent-free estradiol, and estrone. Conversely, risk was decreased with higher levels of percent sex hormone-binding globulin (SHBG)-bound estradiol and SHBG. Analyses conducted prior to adjustment for hormone levels indicated a positive association with body mass index (BMI). After adjustment for estrone level, the positive association of BMI with risk of endometrial cancer was attenuated, suggesting that hormone levels may be an intermediate effect of body weight.[32]

Exogenous estrogen

Postmenopausal hormone therapy (HT)

An association between estrogen replacement therapy and endometrial cancer was reported in 1975 [33] and confirmed soon after.[34,35] In these three studies, the overall risk ratio ranged from 4.5 to 8.0. Further studies documented an association with duration of use (10-fold to 30-fold with 5 years or more of use),[36-39] and a persistent effect lasting more than 10 years after 1 year’s use.[40] When these findings were publicized, prescriptions for estrogen declined sharply, followed rapidly by a drop in endometrial cancer incidence.[41]

Combination estrogen-progestin replacement therapy

Postmenopausal estrogen was long recognized to be associated with the risk of endometrial hyperplasia, often a precursor of endometrial cancer.[42] In addition, progestational agents were known to be effective in the treatment of uterine neoplasms.[43-45] Consequently, improved postmenopausal HT was proposed, combining estrogen and progestin, so as to avoid the endometrial cancer risk associated with unopposed estrogen.[46,47]

The Million Women Study,[49] a cohort study conducted in the United Kingdom in more than one million women aged 50 to 64 years, observed a statistically significant decreased risk of endometrial cancer associated with continuous combined estrogen-progestin therapy, compared with never-users (RR, 0.71; 95% CI, 0.56–0.90). The relative risk with cyclic estrogen-progestin therapy was 1.05 (95% CI, 0.91–1.22), compared with never-users. A similar finding was observed in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort,[50] with a decreased risk associated with continuous estrogen-progestin therapy, but this association was based on only three exposed cases. In the EPIC study, sequential therapy was associated with an attenuated risk of endometrial cancer compared with estrogen-only therapy, but the observed risk was a borderline significant excess risk with sequential therapy (RR, 1.52; 95% CI, 1.00–2.29) compared with never-users.[50] These observed risks were similar to those observed in the NIH-AARP Diet and Health Study Cohort.[51] In that study, fewer than 10 days of estrogen-progestin therapy was associated with a borderline excess risk of endometrial cancer (RR, 1.46; 95% CI, 1.00–2.13), but continuous therapy was associated with a statistically significant decreased risk of endometrial cancer (RR, 0.64; 95% CI, 0.49–0.83).

Tamoxifen and raloxifene are SERMs, drugs that have divergent estrogen agonist and antagonist effects in different target organs. The association between endometrial cancer and tamoxifen was first recognized in 1985, when three cases of endometrial cancer were described in women who had been treated with tamoxifen for breast cancer.[52] Since then, confirmation of the association has been provided by randomized clinical trials using tamoxifen for breast cancer treatment and prevention [53-56] and by case-control, observational, and laboratory studies.

The National Surgical Adjuvant Breast and Bowel Project, Breast Cancer Prevention Trial P-1 Study in women at high risk of invasive breast cancer demonstrated that tamoxifen decreased breast cancer incidence by 49%, but confirmed an increased incidence of endometrial cancer. The annual rate was 2.3 per 1,000 for women receiving tamoxifen versus 0.91 for those on placebo. Women older than 50 years experienced the largest effect. Of the 51 invasive cancers diagnosed in this trial, 50 were stage I.[57]

Raloxifene is a second-generation SERM approved for prophylaxis against postmenopausal osteoporosis. Unlike tamoxifen, it does not have an estrogenic effect on the uterus. The Multiple Outcomes of Raloxifene randomized trial, after 40 months of follow-up, showed that raloxifene reduced the risk of estrogen receptor–positive breast cancer, without increasing endometrial cancer (RR, 0.8; 95% CI, 0.2–2.7).[58] A population-based study of 547 women with endometrial cancer and 1,410 controls was done in Philadelphia, Pennsylvania. Of the cases, 18 (3.3%) had taken raloxifene and 34 (6.2%) had taken tamoxifen (OR, 3.0; 95% CI, 1.3–6.9).[59]

Obesity

Elevated BMI and obesity are associated with an increased risk of endometrial cancer. One of the possible mechanisms for the observed association is an increased level of serum estrone in obese women as a result of aromatization of androstenedione in adipose tissue, which increases the production of estrogen.[60] Alternatively, obesity has been associated with a reduction in levels of SHBG, which may protect against endometrial cancer by decreasing bioavailable estrogen.[61] Obesity has been associated with several factors known to increase the risk of endometrial cancer, including upper-body or central adiposity, polycystic ovarian syndrome, and physical inactivity.[62]

Presumably, body weight is a modifiable risk factor, which accounts for a substantial proportion of endometrial cases worldwide. A study conducted among European countries estimated that between 26% and 47% of endometrial cancer cases can be attributed to overweight and obesity. The same group conducted a meta-analysis of 12 studies (5 cohort and 7 case-control), which examined the relationship between obesity and endometrial cancer. Eleven of the 12 studies concluded that there is a positive association between endometrial cancer and excess weight.[63]

RRs associated with obesity range from 2 to 10. Some studies show that upper-body and central weight confer a higher risk than peripheral body weight, even after consideration of BMI.[64-66] However, other studies have failed to confirm such an association. Several studies have observed a stronger association between endometrial cancer and obesity near the time of diagnosis compared with obesity earlier in life.[67-70]

Increasing age

Endometrial cancer primarily affects postmenopausal women, with a median age at diagnosis of 60 years.[2]

Interventions of Unproven or Disproven Effect on Risk

Weight loss

While it is known that obesity is associated with increased endometrial cancer risk, only one study examines the potential benefit of intentional weight loss. In the Iowa Women’s Health Study of 21,707 postmenopausal women,[71] participants completed a self-report questionnaire, about intentional weight loss between ages 18 and 39 years, between ages 40 and 54 years, and after age 55 years. Multivariate models adjusting for age, BMI, and BMI2 found no association between endometrial cancer incidence and intentional weight loss of at least 20 lbs (RR, 0.93; 95% CI, 0.60–1.44). The obvious limitation of this study is the reliance on retrospective self-reported data.[71]

Fruits, vegetables, and vitamins

The association between dietary factors, particularly fruit and vegetable intake, and endometrial cancer has been evaluated primarily in case-control studies. A systematic review of the evidence was undertaken as part of the World Cancer Research Fund’s Food, Nutrition, Physical Activity and Cancer: A Global Perspective (2006) report. A pooled OR from ten case-control studies for high versus low vegetable intake was 0.71 (95% CI, 0.55–0.91).[72] This association was similar to that reported previously in a report for the International Agency for Research on Cancer,[73] which was based on results from five case-control studies. Neither report observed evidence of an association between fruit intake and endometrial cancer.

There is case-control evidence suggesting that regular consumption of soy products reduces the risk of endometrial cancer.[74,75]

A consortium of seven prospective cohort studies examined the association between serum vitamin D levels and the development of endometrial cancer. After controlling for BMI, there was no evidence of an association between circulating vitamin D and risk of endometrial cancer.[76]

Multivitamin use has little or no influence on the risk of common cancers, including endometrial cancer, or on total mortality in postmenopausal women.[77]

References

American Cancer Society: Detailed Guide: Endometrial Cancer: What are the Risk Factors for Endometrial Cancer? Atlanta, Ga: American Cancer Society, 2005. Available online. Last accessed December 3, 2014.

Combination oral contraceptive use and the risk of endometrial cancer. The Cancer and Steroid Hormone Study of the Centers for Disease Control and the National Institute of Child Health and Human Development. JAMA 257 (6): 796-800, 1987. [PUBMED Abstract]